Leptin is a polypeptide hormone predominantly expressed by adipose tissue and is involved in the regulation of metabolism, energy balance and food intake. Leptin activity is mediated by interaction with, and signaling through, the leptin receptor. Leptin receptor, (also known as “LEPR,” “WSX,” “OB receptor,” “OB-R,” and “CD295”) is a single-pass transmembrane receptor of the class I cytokine receptor family with a large (818 amino acid) extracellular domain. Elevated expression of leptin, the Ob-R leptin receptor or both can contribute to multiple disorders including, but not limited to, anorexia or other psychiatric eating disorders, chronic kidney disease cachexia, other cachexias such as congestive heart failure cachexia, pulmonary cachexia, radiation cachexia, and cancer cachexia, autoimmune disorders such as inflammatory bowel disease, lupus erythematosus, multiple sclerosis, psoriasis, cardiovascular diseases, elevated blood pressure, depression, nonalcoholic fatty liver disease, neurodegenerative disorders, depression, cancer such as hepatocellular carcinoma, melanoma and breast cancer.
Proposed therapeutic approaches for addressing high leptin signaling include use of leptin receptor peptide antagonists and antagonist mutants such as soluble leptin receptor variants, competitive LEPR antagonists such as antibody 9F8 (Fazeli et al. (2006) J Immunological Methods 312, 190-200) or nanobodies targeting leptin receptor (McMurphy et al., PLOS One (2014) 9(2):e89895), fibronectin III domains, orexigenic substances (e.g., ghrelin and NPY), blockade of leptin's downstream mediators (e.g., melanocortin receptor 4) and/or lifestyle changes. Such approaches, however, have generally shown limited efficacy. Thus, a need exists in the art for alternative approaches to treating leptin resistance and other conditions associated with elevated serum leptin levels, and/or excessive LEPR signaling.